One of the key issues in chemistry is chemical stability. If chemical stability could be reliably predicted by computational methods, then real molecular engineering could be achieved being able to design stable molecules or molecular complexes having desirable properties rationally. One of the most important industries recently endeavored in molecular engineering is the pharmaceutical industry. Thanks to recent advances in molecular biology, the three-dimensional molecular structures of many biological target proteins are now known and it has been assumed that knowledge of the structure of the target protein could be used to rationally select the most active hypothetical molecules for actual synthesis for testing their applicability as potential drugs. The key factor of the activity of a drug molecule is the stability of its complex with a particular protein. The stability of the complex is measured by the binding free energy. The prediction of the relative binding energies of different drug candidates with respect to the same protein host is one of the most sought after hopes of the pharmaceutical industry. There, chemists often hypothesize dozens of molecules they might synthesize but have trouble deciding which ones have the best chance of being highly active in some biological assay. Computational techniques that help the chemists selecting the most promising candidates for synthesis are extremely valuable. Unfortunately, the thermodynamics of binding is quite complex (see, e.g. Gilson, M. K.; Given, J. A.; Bush, B. L.) and using the state-of-the-art arsenal of computational methods requires very long computer simulations (Kollman, P. A. 1993).
For calculations of the relative binding energies of different drugs for a given protein receptor to work properly, many different things have to be done correctly. In particular, the gas phase potential energy force field has to be accurate, the effect of solvent has to be included in some realistic and efficient way, and all the vibrational and conformational states of the system have to be sampled with the correct Boltzmann weights. This last issue is known as the sampling problem and is a particularly difficult one to solve because the drug-receptors complex may exist in many different conformations. Furthermore, these different conformations may be separated by large energy barriers that prevent these conformations from being interconverted using traditional simulation methods. Recent studies (e.g. van Gunsteren and Mark,1992) suggest that the length of contemporary free energy simulations of flexible biological molecules may be orders of magnitude too short for convergence and any agreement with experiment may be only fortuitous (i.e. not predictive). The invention described here should provide a solution to this problem by affording a direct method for the calculation of conformational and binding free energies without the need for expensive simulations.
Chemical stability can always be formulated in terms of conformational free energy (CFE) differences. There can be various levels envisioned at which approximations to CFE differences can be made. For example, if one wishes to calculate the anomeric free energy for the equilibrium of .alpha. and .beta. anomers of monosaccharides, then the simplest approach one can follow is to calculate the energy difference between the lowest energy .alpha. and the lowest energy .beta. anomer. Of course, this approach ignores entropic effects due to the fact that there are multiple conformations of both the .alpha. and .beta. anomers and that the individual conformations are not static (confined to the bottom of their energy well) but exhibit large dynamic diversity in terms of conformational changes limited to that energy well. Note that glucose, for example, possesses literally hundreds of low-energy conformations of both anomeric states.
Throughout this application, the following references are referred to by name and date within parentheses in the text; disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.